Metronidazole (1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole) and tinidazole (1-[2-(ethylsulfonyl)ethyl]-2-methyl-5-nitroimidazole) are synthetic nitroimidazole antimicrobial agents, which have been useful for the treatment of bacterial vaginosis (BV) and vaginal trichomoniasis. Both compounds exhibit activity against Trichomonas vaginalis, Giardia duodenalis, and Entamoeba histolytica protozoa and are also active against bacterial vaginosis pathogens such as Bacteriodes species, Peptostreptococcus and other anaerobes. In addition, metronidazole has been used in the treatment of rosacea, acne and other inflammatory skin conditions. Nitroimidazoles have been used to treat a variety of conditions including vaginal disorders and protozoal disorders.
U.S. Pat. No. 5,536,743 to Borgman describes a pH buffered, aqueous gel formulation of the antimicrobial agent metronidazole for treatment of bacterial vaginosis. Metronidazole has very limited solubility in water (less than about 1 percent by weight in water at neutral pH), so compositions containing metronidazole at concentrations of about 1 percent by weight or greater, generally include insoluble metronidazole crystals or must include organic co-solvents, cyclodextrins or water-soluble vitamins to aid in the solubilization of the metronidazole.
Tinidazole has a similarly limited solubility in water (about 0.45 percent by weight at neutral pH). It is difficult to obtain stable, physiologically-acceptable aqueous tinidazole solutions at concentrations above about 0.45 percent by weight, which are free from tinidazole crystals.
There is an ongoing need for aqueous nitroimidazole solutions that include a greater concentration of nitroimidazole (e.g., metronidazole and/or tinidazole) than the solubility limit in neutral water, which are free from organic co-solvents, water-soluble vitamins, and cyclodextrins, and free from undissolved nitroimidazole crystals. The present invention provides such aqueous nitroimidazole compositions.